Process for preparing 5-oxa PGF1.sub.α -type compounds

ABSTRACT

Process for making 5-oxa prostaglandin F 1 .sub.α -type compounds. These compounds are useful for a variety of pharmacological purposes, including inhibition of platelet aggregation, increase of nasal patency, and labor inducement at term.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of my co-pending application Ser. No. 361,991 filed May 21, 1973 now U.S. Pat. No. 3,931,279.

BACKGROUND OF THE INVENTION

This invention relates to novel compositions of matter, to novel methods for producing those, and to novel chemical intermediates useful in those processes. Particularly, this invention relates to a process for preparing certain novel analogs of prostaglandin F₁.sub.α in which the C-5 methylene (--CH₂) in the prostanoic acid structure is replaced by oxygen (--O--), represented by the formula: ##STR1## wherein the terms O, R₂, R₃, R₄, R₄, R₂₅, and R₂₆ are defined herein.

The essential material for this application, including the background of the invention, the disclosure of the invention, and the description of the preferred embodiments, including Preparations and Examples, is incorporated by reference from U.S. Pat. No. 3,931,279 columns 1-67 and 73-86, inclusive, under the provisions of M.P.E.P. 608.01(p).

SUMMARY OF THE INVENTION

It is a purpose of this invention to provide novel 5-oxa prostagalandin E, F, A, and B analogs. It is a further purpose to provide novel 5-oxa prostaglandin analogs with a variety of substituents and degrees of saturation in the side chains. It is a further purpose to provide 5-oxa prostaglandin analogs having the 11-deoxy ring-structure in which the 11-hydroxy is replaced by hydrogen. It is a further purpose to provide esters, lower alkanolates, and pharmacologically acceptable salts of said analogs. It is a further purpose to provide novel processes for preparing said analogs and esters. It is still a further purpose to provide novel intermediates useful in said processes.

The novel prostaglandin analogs of this invention each have an oxygen (--O--) in place of the methylene (--CH₂ --) moiety at the 5-position of the prostanoic acid formula. They are represented by the generic formula ##STR2## wherein is one of the six carbocyclic moieties: ##STR3## wherein ˜ indicates alpha or beta attachment of hydroxyl to the cyclopentane ring; wherein E is --CH₂ CH₂ -- or ##STR4## wherein Q₁ is ##STR5## or ##STR6## wherein R₆ and R₇ are hydrogen or alkyl of one to 4 carbon atoms, inclusive, being the same or different; wherein R₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive; wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro; wherein R₂ is hydrogen or fluoro, with the proviso that R₂ is fluoro only when R₃ is hydrogen or fluoro; wherein R₄ and R₅ are hydrogen or alkyl of one to 4 carbon atoms, inclusive, being the same or different with the proviso that no more than one of R₃, R₄, and R₅ is alkyl; and wherein R₁₄ is (1) ##STR7## with the proviso that R₁₄ is ##STR8## only when E is ##STR9## ; wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₈ R₉ -- and terminal methyl; wherein R₈ and R₉ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that R₉ is fluoro only when R₈ is hydrogen or fluoro; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₁₀, wherein R₁₀ is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl; and wherein Z represents an oxa atom (--O--) or C_(j) H_(2j), wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, with one to 6 carbon atoms, inclusive, between --CR₈ R₉ -- and the ring. 

I claim:
 1. A process for preparing an optically active compound of the formula ##STR10## or a racemic compound of that formula and the mirror image thereof, wherein Q₂ is ##STR11##wherein R₃ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro; wherein R₂ is hydrogen or fluoro, with the proviso that R₂ is fluoro only when R₃ is hydrogen or fluoro; wherein R₄ and R₅ are hydrogen or alkyl of one to 4 carbon atoms, inclusive, being the same or different, with the proviso that not more than one of R₃, R₄, and R₅ are alkyl; wherein R₂₅ is ##STR12##wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR₈ R₉ -- and terminal methyl, wherein R₈ and R₉ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that R₉ is fluoro only when R₈ is hydrogen or fluoro, or ##STR13##and wherein R₂₆ is alkyl of one to 3 carbon atoms, inclusive; which comprises starting with an optically active compound of the formulaa. condensation with an omega-halo ortho ester of the formula ##STR14##wherein Hal is chloro, bromo, or iodo, and wherein R₂, R₃, R₄, R₅, and R₂₆ are as defined above, in the presence of a base selected from the class consisting of n-butyllithium, phenyllithium, triphenylmethyllithium, sodium hydride, and potassium t-butoxide, and, when the base is an organolithium compound, in dimethyl formamide or hexamethylphosphoramide; b. transformation of the product of step a) to an optically active compound of the formula ##STR15##or a racemic compound of that formula and the mirror image thereof, wherein Q₃, R₂, R₃, R₄, R₅, R₁₃, R₂₅, and R₂₆ are as defined above, by hydrolysis; and c. replacement of the R₁₃ groups with hydrogen, by hydrolysis.
 2. The process of claim 1 wherein the condensation of step a) is done in the presence of potassium t-butoxide.
 3. The process of claim 1 wherein the condensation of step a) is done in the presence of n-butyllithium and hexamethylphosphoramide.
 4. A process according to claim 1 wherein R₃, R₄, and R₅ are either hydrogen or methyl, and at least one of R₃, R₄, and R₅ is methyl.
 5. A process according to claim 1 wherein R₂, R₃, R₄, and R₅ are hydrogen.
 6. A process according to claim 5 wherein R₈ and R₉ are either hydrogen or methyl, and at least one of R₈ and R₉ is methyl.
 7. A process according to claim 5 wherein C_(g) H_(2g) is trimethylene.
 8. A process according to claim 5 wherein R₂₅ is ##STR16##
 9. A process according to claim 5 wherein R₂₅ is --(CH₂)₄ --CH₃.
 10. A process according to claim 5 wherein R₂₅ is ##STR17## 